Project Summary: How biomolecules behave and interact with partners in its crowded environment must be considered for any realistic representation of biomolecular interactions in the cell. A model system that captures these important features of the cell is the ribosome exit tunnel. As a protein becomes synthesized by the ribosome, the newly formed nascent peptide chain must traverse a narrow tunnel in the ribosome, which is composed of a myriad of RNA, protein, and water molecules. In our proposed research, we will study the dynamics of a nascent peptide chain as it traverses the ribosome exit tunnel using a coarse-grained representation of the surrounding RNA and protein molecules. We will address the interactions of the nascent peptide chain with the heterogeneous mixture of biomolecules in the confined environment. Once the protein leaves the ribosome exit tunnel, we will study how the protein avoids aggregation that will lead to disease and death due to a failure to perform its function. We will begin by developing a physical-bioinformatical based recognition code of proteins and RNA interactions that takes into consideration water-mediated interactions. The code will be introduced into coarse-grained physical models for detailed molecular dynamics simulations of protein-RNA complexes. The next step will be to simulate a nascent peptide as it traverses through the crowded ribosome exit tunnel, which is comprised of the RNA and protein molecules. We will focus where in the crowded tunnel and under what conditions the nascent peptide chain may form secondary structure. Finally, we will simulate multiple nascent peptide chains to address how the protein chains in high concentration do not aggregate. Relevance: A physical, microscopic view of biological interactions in the cell is fundamental to our understanding of underlying processes. We will develop coarse-grained models to study the protein-RNA interactions to study how a newly formed protein leaves the ribosome to perform its function. Failure to successfully leave the proximity of the ribosome will lead to an inability of the cell to work, leading to disease and death.